The head of the global nuclear watchdog, Yukiya Amano, has died at the age of 72, the agency announced.
He has led the International Atomic Energy Agency (IAEA) since 2009, and was due to step down in March because of an unspecified illness.
During his tenure he had overseen a period of tense negotiations regarding Iran's nuclear programme.
It is not yet clear who will succeed him, though discussions over his replacement began last week.
The Japanese national had taken over from Mohamed ElBaradei a decade ago and his third term was due to run until November 2021.
However, Amano appeared increasingly frail after undergoing an unspecified medical procedure in September.
"The Secretariat of the International Atomic Energy Agency regrets to inform with deepest sadness of the passing away of Director General Yukiya Amano," the IAEA statement said.
EU foreign policy chief Federica Mogherini spoke of her sadness at Amano's passing.
"A man of extraordinary dedication & professionalism, always at the service of the global community in the most impartial way. I'll never forget the work done together. It has been for me a great pleasure & privilege working with him," she tweeted.
The agency said the flag over its head office in Vienna had been lowered to half-mast.
Who was Yukiya Amano?
Amano was regarded as more reserved and technocratic than his outspoken predecessor, who regularly clashed with US officials over its policies on Iran.
Some diplomats expressed frustration behind closed doors over the lack of sensitive confidential information Amano would share in comparison to Mr ElBaradei.
Amano joined the Japanese foreign ministry in 1972 and held increasingly senior positions, notably as director of the science division and director of the nuclear energy division.
He served as chairman of the IAEA's policy-making board of governors in 2005-06 when the agency and Mr ElBaradei were jointly awarded the Nobel Peace Prize.
Amano was narrowly elected as the agency's head in 2009, backed by Western powers, in an election race that highlighted a deep divide between industrialised and developing nations on the IAEA's board.
Who will be next IAEA chief?
No decisions have been made yet, but the race started last week as it became clear Amano would be stepping down.
Names being touted include Argentina's ambassador to the IAEA, Rafael Grossi, and diplomats say the agency's chief coordinator, Cornel Feruta of Romania, is likely to put himself forward.
Whoever takes the role, no major policy shifts are expected regarding the most pressing issues including Iran and the possibility of returning to North Korea, which removed IAEA inspectors ten years ago.